Novel steroids of the androstane series



United States Patent 3 287,357 NOVEL STEROIDS OF THE ANDROSTANE SERIESWilliam J. Wechter and Fred Kagan, Kalamazoo, Mich., assignors to TheUpjohn Company, Kalamazoo, Mich., a corporation of Delaware No Drawing.Filed Dec. 16, 1963, Ser. No. 330,560 11 Claims. (Cl. 260-23955) Thisinvention relates to novel steroids of the androstane series.

The novel compounds of this invention are produced 10 according to thefollowing reaction scheme:

lce 3,287,357

9H i l H0- I XVa 1'13 Tos-O- III QH T Tos-0 IV Patented Nov. 22, 1966sisting of l i? T Q R1" R1" O- Tos-0 H V 3 XII H H R2 a R2 B:

i T I 1 R, It l E v: \/i 5 H H R2 3 R2 a ll no" 11-0-0 5 z VII XIV I Hli H 5 f R: R, Y= 0=0 R, R, l

7 e K O 9 HO 1 HO 1 R,- R1

'-i no" HO-- l VIII IX H H R: .R3 7 R: 'R;

wherein R is selected from the group consistingof hydrogen and fluoro,vwith the proviso that when R is fluoro R and R are hydrogen'and X isselected from the group consisting of and Y is selected from the groupconsisting of CH and C=O;' R is selected from the group consisting ofhydrogen and methyl, with the proviso that when R is methyl R and Rarehydrogen and X and Y are CH R is selected from the group consistingof hydrogen and methyl, with the proviso that when R is methyl R and andY is selected from the group consisting of CH and C=O; and when R R andR are hydrogen X is selected from the group consisting of H and Y isO=O; Ac is the acyl radical of an organic carboxylic acid, preferably ahydrocarbon carboxylic acid containing from 1 to 12 carbon atoms,inclusive; R is an alkylene radical containing not more than 8 carbonatoms, inclusive, and the attaching oxygen to carbon bonds are separatedby a chain of at least 2 and not more R are hydrogen, X is, selectedfrom the group con than 3 carbon atoms; and Tos is the tosyl radical,preferably the p-tosyl radical.

The novel compounds of Formulae Hat, 11 8, III, IV, V, VI, VII, VIII,IX, X, XI, XII, XHI, XIV, XVoz and XVB possess therapeutic propertiesuseful in the treatment of animals, such as mammals and birds, and areparticularly useful in the treatment of valuable domestic animals.

Each possesses for example, hypocholesteremic activity. In addition eachpossesses hypolipemic, antiatherosclerotic, anticoronary thrombolytic,antiartery plaque deposition and antihypertensive activity.

The compounds of Formula XIII, in addition to the activities statedabove, also possess anti-estrogenic activity.

Administration of the compounds of Formulae He, He, III, IV, V, VI, VII,VIII, IX, X, XI, XII, XIII, XIV, XV and XVB can be in conventionaldosage forms, such as pills, tablets, capsules, syrups, or elixirs fororal use, or in liquid forms which are suitable for injectable products.They can also be administered topically in the form of ointments,creams, lotions, and the like, with or without coacting antibiotics,germicides or other materials forming advantageous combinationstherewith.

The novel products of this invention are produced by a process whichcomprises treating the compounds of Formula I, such asZea-fluoro-l7,8-hydroxy-5a-androstan- 3-one l7-acetate with a reducingagent to obtain the com pounds of Formula Hot and 115, such as2a-fiuoro-3a,17fi-dihydroxy-5a-androstane 17-acetate and2a-fiuoro-3B,17fi-dihydroxy-5u-androstane 17-acetate, re

spectively.

The conversion of the compounds of Formula I to the compounds ofFormulae Ila and H5, Reaction 1, is carried out using a reducing agent,for example, lithium aluminum tri-t-butoxide hydride, sodiumborohydride, diborane, lithium aluminum triethoxy hydride, potassiumborohydride, and the like, in an inert organic solvent, for example,lithium aluminum tri-t-butoxide hydride in tetrahydrofuran, ether,diglyme, and the like. Advantageously the reaction is carried out attemperatures from to 100 C. for A to 2 hours with a temperature of 25 C.for /2 hour being preferred. The compounds of Formulas Ila and 11B arerecovered following Reaction 1 by fractional crystallization,chromatography of the total crude reaction product on acid Washedalumina Florisil (synthetic magnesium silicate) silica gel, or silicicacid, eluting with commercial hexanes containing increasing amounts ofacetone or benzene containing increasing amounts of methanol, Craigcountercurrent partition separation, column partition chromatography,preparative paper chromatography, thin-layer chromatography, or acombination of these.

Reaction 2, the conversion of the compounds of Formula Ha, such as2a-fluoro-3a,17/3-dihydroxy-5u-androstane 17-acetate, to the compoundsof Formula III, such as 2a-fluoro-3u,l7fi dihydroxy-5tit-androstane3-dihydropyranyl ether l7-acetate is carried out by reacting thestarting steroid of this step with dihydropyran in the presence of aLewis acid, such as boron trifluoride etherate, p-toluenesulfonic acid,sulfuric acid, zinc chloride, and the like. Advantageously, the reactioncan be carried out in the presence of an organic solvent, such as ether,benzene, and the like. The reaction is carried out at temperatures offrom 0 to 80 C., with a temperature of 25 C. being preferred. Thethus-obtained compounds of Formula III are recovered from the mixture byconventional methods, such as, for example, dilution of the reactionmixture with water, extraction with a water immiscible solvent, such asmethylene chloride, ethyl acetate, benzene, toluene, and the like, orany of the methods described above for the recovery of the compounds ofFormulas Hot and I1 8. Alternatively, the entire crude product obtainedfrom Reaction 2 can be used in the subsequent hydrolysis step, Reaction3,

Reaction 3, the hydrolysis of the compounds of Formula HI, such as2ot-fluoro3a,17fi-dihydroxy-5u-androstane I i-dihydropyranyl ether17-acetate, to the compounds of Formula IV, such as2u-fiuoro-3a,l7}3-dihydroxy-5aandrostane S-dihydropyranyl ether, iscarried out in an alkaline aqueous medium using relatively water solublealkali metal carbonates, alkaline earth metal carbonates, alkali metalhydroxides, alkaline earth hydroxides, e.g., sodium or potassiumcarbonate, calcium carbonate, so-

dium or potassium hydroxide, calcium hydroxide, and the like, preferablypotassium carbonate. Advantageously there is added to the alkalineaqueous medium an inert water-miscible organic solvent, such asmethanol, ethanol, isopropyl alcohol, and the like, with methanol beingpreferred. The reaction is carried out at temperatures of 10 to C. for 1to 20 hours. The compounds of Formula IV are recovered from the reactionmixture by the methods described above for the recovery of the compoundsof Formula III. Alternatively, the crude compounds of Formula IV(wherein the group at the '11- position is CH or C=0) can be used in thesubsequent oxidation step, Reaction 4.

Reaction 4, the oxidation of the compounds of For- 'mula IV (wherein thell-group is CH or C=O),

such as 2a-fluoro-3 a,17(3-dihydroxy-5a-androstane 3-dihydropyranylether, to the compounds of Formula V, such as 20: fiuoro3a-hydroxy-5a-androstan-17-one 3-dihydropyranyl ether is carried out byreacting the starting steroid of this step with an oxidizing agent inthe presence of an organic solvent. Suitable oxidizing agents arechromic anhydridepyridine complex, chromic anhydride/sulfuric acid,sodium dichromate, and the like, and suitable solvents are pyridine,acetone, acetone-water, and the like, with chromic anhydride-pyridinecomplex being preferred. The reaction is carried out at temperatures of0to 50 C. for 2 to 20 hours. The compounds of Formula V are recoveredfrom the reaction mixture by the methods described above for therecovery of the compounds of Formula III. Alternatively, the crudecompounds of Formula V can be used in the subsequent step, the removalof the dihydropyranyl ether group, without further purification.

Reaction 5, the removal of the dihydropyranyl ether group, is carriedout by treating the compounds of Formula V, such as i 2oz fiuoro3ot-hydroxy-5a-androstan-17-one 3 -dihydropyanyl ether,

with an acid in the presence of an organic solvent to obtain thecompounds of Formula VI, such as Zoe-fluOIO-3ot-hydroxy-5ot-androstan-l7-one. Preferably the acid is a mineral acid,such as hydrochloric, hydrobromic, sulfuric acids, and the like.Suitable solvents are acetonewater, methanol-water,dimethylsulfoxide-water, dir'nethylformamide-water, and the like. Thereaction is conveniently carried out at a temperature of 10 to 50 C. forfrom 5 to 50 hours. The compounds of Formula VI are recovered from thereaction mixture by the methods described above for the recovery of thecompounds of Formula III.

Reaction 6, the formation of the 17-ethylene ketal, is carried out bytreating the compounds of Formula VI, such as2a-fl-uoro-3a-hydrOXy-Sa-androstan-17-one, with ethylene glycol, in thepresence of a strong acid such as p-toluenesulfonic acid,ortho-chlorobenzenesulfonic acid, sulfuric acid, and the like, toproduce the compounds of Formula VII, such as 2a-fluoro-3u-hydroxy-5ot-androstan-17 one 17 ethylene ketal. i i i Similarly the compounds ofFormula VI can be allowed wherein n is an integer having a value fromone to two inclusive, R and R each represent hydrogen or lower alkylradicals containing up to six carbon atoms and wherein the total numberof carbon atoms in the alkane diol is up to and including 8 carbonatoms, to obtain the corresponding 17-alkylene ketals of Formula VII.Advantageously the l7-ketalization is carried out in the presence of anorganic solvent such as benzene, toluene, xylene, and the like. Thecompounds of Formula VII are recovered from the reaction mixture by themethods described above for the recovery of the compounds of Formula HI.Alternatively, the crude product of Reaction 6, the compounds of FormulaVII where the ll-group is keto, can be used in the subsequent reductionstep.

Reaction 7, the reduction of the ll-keto group to the llfl-hydroxy.group, is carried out by treating the compounds of Formula VII wherethe ll-group is keto, such as 2a-fluoro-3m-hydroxy-5a-androstane 11,17dione 17- ethylene ketal, with a reducing agent to obtain the compoundsof Formula VIII, such as 2a-fluoro-3u,-11B-dihydroxy-5a-androstan-17-one17-et-hylene ketal. Suitable reducing agents are lithium aluminumhydride, sodium borohydride, potassium borohydride, diborane, and thelike. The reaction is carried out in an inert organic solvent, such astetrahydrofuran, ether, diglyme, and the like, at temperatures of from20 to 100 C. for 1 to 80 hours. Similarly other ll-keto l7-alkyleneketals can be substituted for the ll-keto 17-ethylene ketals describedabove to yield the corresponding llp-hydroxy 17-alkylene ketals. Thecompounds of Formula VIII are recovered from the reaction mixture by themethods described above for the recovery of the compounds of FormulaIII. Alternatively, the crude product of Reaction 7 can be used in thesubsequent deketalization step. Reaction 8, the deketalization step, iscarried out by treating the compounds of Formula VIII, such as2afiuor-o- 3a,llfl-dihydroxy-M-androstan-l7-one 17-ethylene ketal withan acid, such as acetic acid, dilute mineral acids, e.g., hydrochloricand sulfuric acids, and the like, to obtain the compounds of Formula IX,such as 20:- fluoro-3a,11B-dihydroxy-5a-androstan-l7-one. The reactionis carried out at temperatures of from 10 to 50 C. for 2 to 20 hours.The compounds of Formula DC are recovered from the reaction mixture bythe methods described above for the recovery of the compounds of FormulaIII.

Reaction 9, the formation of the 3-tosylate, is carried out by reactingthe compounds of Formula 11,8, such as2u-fluoro-3;3,l7fi-dihydroxy-5mandrostane 17-acetate with morp-toluenesulfonyl chloride, preferably p-toluenesulfony-l chloride, inthe presence of a weak base, such as pyridine, collidine,dimethylaniline, and the like, to obtain the compounds of Formula X,such as 2a-fluoro- 3;B,17B-dihydroxy-5u androstane 3 tosylate 17acetate. The reaction is carried out at a temperature of 10 to 50 C. for2 to 50 hours. The compounds of Formula X are recovered from. thereaction mixture according to the procedures described above for therecovery of the compounds of Formula III.

Reaction 10, the conversion of the 3-tosy1ate 17-acetate to the3-tosylate 17 alco'hol, is carried out by treating the compounds ofFormula X, such as 2a-fluoro-3fl,17/3-dibydroxy-5u-androstane-3-tosylate17-acetate with a Lewis acid, such as hydrochloric, hydrobromic,sulfuric acids, boron trifluoride, and the like, in the presence of an.alkanol, such as methanol, ethanol, and the like, to obtain thecompounds of Formula XI, such as 2a-iiuoro-35,17,8-dihydroxy-M-androstane 3-tosylate. The reaction is carried out attemperatures of from 0 to 50 C. for 5 to 50 hours. The compounds ofFormula X are recovered from the reaction mixture according toprocedures described above for the recovery of the compounds of FormulaI11. Alternatively, the crude compounds of Formula XI can be used in thesubsequent oxidation step without further purification.

Reaction 11, the oxidation of the compounds of Formula XI, such as2a-fluoro-3fi,17;3 dihydroxy 5oz androstane 3-tosylate, to produce thecompounds of For? mula XII, such asZen-fluor-o-3B-hydroxy-5u-androstan-17- one 3-tosylate, is carried outin the manner described above for the production of the compounds ofFormula V from the compounds of Formula IV.

In Reaction 12, the compounds of Formula XII, such as2a-fl-uoro-3fi-hydroxy-sot-androstan-l7-one 3-tosylate are treated witha mixture of dimethylformamide and an alkali metal formate, such assodium, potassium or lithium formate, at a temperature of 60 to 220 C.for 2 to 70 hours to produce a mixture of the compounds of Formula XIII,such as 2-fluoro-5u-androst-2-en-17-one, and Formula XIV, such as2a-fluoro-3 u-hydroxy-5a-androstan- 17-one 3-formate. In those instanceswhere the 3-formylation proceeds more easily, i.e., when R is hydrogen,the alkali metal formate can be omitted from the reaction and a reactiontemperature of 85 C. for 2 to 5 days can be used.

In Reaction 13, the mixture comprising the compounds of Formula XIII,such as 2-fluoro-5a-androst-2-en-17-one, and Formula XIV, such as2a-fluoro-3u-hydwXy-Sa-am drostan-17-or1e 3-forrnate, is subjected tochromatography during which the compounds of Formula XIV are convertedto the compounds of Formula VI, ,such as20cfluoro-3ot-hydroxy-5ot-audrostan-l7-one, while the compounds ofFormula XIII remain unchanged. The chromatography also effects theseparation of the compounds of Formulas XIII and VI from each other. Thecornpounds of Formulas XIII and VI can be further purified using themethods described above, e.g., tfurther chromatography,recrystallization and the like.

Reaction 14, the conversion of the compounds of Formula Ha, such as2a-fluoro-3a,l7fi-dihydroxy-5a-androstane l7-acetate, and H5, such asZa-flubro-Bdflfi-dihydroxy-Sa-andmstane 17-acetate, to the compounds ofFormulas XV 0:, such as Zot-fluoro-Sa,l7fl-dihydroxy-5a-androstane, andXVB, such as 2a-fluoro-3/5',l7fl-dihydroxy- Swandrostane, is carried outaccording to procedures well known in the art for the conversion ofandrostane 17-acylates to androstane l7-alcohols as shown in US. Patent2,849,464.

The following preparations and examples illustrate the best methodcontemplated by the inventors for carrying out their invention.

PREPARATION 1 1 1 -Ketorestosterone A solution is prepared containing in100 ml. of pyridine 10 g. of llB-hydroxytestosterone and 50 ml. ofacetic anhydride. The solution is allowed to stand at room temperature(about 24 C.) for a period of 18 hours and is then poured into 1000 ml.of ice water. The aqueous mixture is allowed to stand overnight andrefrigerated between 0 to 5 C. and is thereupon filtered the next dayand the precipitated material, thus collected, is twice recrystallizedfrom aqueous methanol to give pure llfi-hydroxytestosterone l7-acetate.

A solution is prepared containing in 100 ml. of acetic acid 6 g. of thethus obtained llB-hydroxytestosterone 17- a-cetate, 3 g. of chromi eanhydride and 4 ml. of water. This mixture is allowed to stand at roomtemperature for a period of 4 hours Whereafter 20 ml. of methanol isvadded. The thus obtained mixture is then poured into 1000 ml. of waterand ice and the aqueous portion extracted with three 300-ml. portions ofmethylene chloride. The methylene chloride extracts are combined, washedwith dilute sodium bicarbonate solution and water, dried over anhydroussodium sulfate, evaporated, and three times recrystallized from aqueousmethanol to obtain 11- ketotestosterone 17-acetate.

A solution is prepared of 3 g. of the thus obtained 11-ke-totestosterone l7-acetate in 200 ml. of one normal sodium hydroxidein percent methanol-l0 percent water. The resulting mixture is allowedto stand at room temperature for a period of 6 hours and thereuponpoured PREPARATION 2 2a-Fluor0-1 7,8-Hydrxy-4-Andr0sten-3-One To asolution of 5.76 g. of testosterone in 100 ml. of tertiary butyl alcoholat 65 C. was added 5.45 ml. of ethyl oxalate and 6.67 ml. of commercial25% sodium methoxide in methanol. After stirring for one-half hour, thenow deep green solution was cooled to 25 -30 C. and 300 ml. or ether wasadded. The sodium enolate of2-ethoxyoxalyl-17,8-hydroxy-4-androsten-3-one which precipitated wasfiltered in a dry atmosphere and dried in a vacuum desiccator overcalcium chloride for about 3 hours.

The dried sodium enolate was then dissolved in 170 ml. of methanol, thesolution cooled to 10 C. and to it was then slowly added an ice-coldsolution of 3.2 g. of perchloryl fluoride in 100ml. of methanol. Thesolution was stirred for 15 minutes. The thus-produced 2-fluoro-2-ethoxyoxalyl-17fi-hydroxy 4 androsten-3-one was decomposed by adding7.0 ml. of 25 methanolic sodium methoxide to the solution. Afterone-half hour, ten drops of acetic acid was added, the solution filteredand the filtrate concentrated on a warm-water bath under reducedpressure to about a third of the original volume. The concentrate wasdiluted to about one liter with cold water and after about an hour theresulting precipitate was collected, washed with water, and dried in avacuum desiccator. The 4.58 g. of Zea-fluoro-17fi-hydroxy-4-androsten-3-one thus obtained was purified by chromatography on a. column of 200g. of magnesium silicate which was eluted with hexanes plus 10% acetone.Two recrystallizations from acetone gave solvated2a-fiuoro-17fl-hydroxy-4-androsten-3-one melting at 161162 C. afterlosing the solvent of crystallization at 110 C.

Analysis.Calcd. :for C I-I FO C, 74.47; H, 8.88; F, 6.2. Found: C,74.54; H, 9.12; F, 6.3.

Following the procedure of Preparation 2 but substituting astoichiometric equivalent weight of 115,17fi-dihydroxy-4-androsten-3-one(115-hydroxytestosterone) as starting compound, there is thus produced2a-fluoro-11B, 17B-dihydroxy-4-androsten-3-one.

Similarly, 17B-hydroxy 4 androstene-3,11-dione (11- ketotestosterone) isconverted to 2a-fluoro-17B-hydroxy 4-androstene-3,11-dione.

PREPARATION 3 Zu-FluOro-l 7 ,B-H ya r0xy5 oc-A ndr0stan-3-One A solutionof 5.0 g. of 2 x-fiuoro-17fi-hydroxy-4-androsten-3-one in 190 ml. of 95%ethanol containing 0.5 ml. of palladium on charcoal catalyst and 0.5 ml.of concentrated hydrochloric acid was shaken in an atmosphere ofhydrogen at 2 atmospheres pressure. The theoretical amount of hydrogenwas absorbed within a fiew minutes. After removing the catalyst byfiltration through a bed of diatomaceous earth, the clear, colorlesssolution was evaporated to dryness on a warm water bath at reducedpressure. The residue was dissolved in methylene chloride and passedover -a column of 200 g. of magnesium silicate (Florisil). The columnwas eluted with 400-ml. fractions; the first eight consisting of hexanes(Skellysolve B) plus 5% acetone and the next eight consisting of hexanesplus 8% acetone. Fractions 10 to contained 2.26 g. of crystallineproduct which was crystallized twice from a mixture of ethyl acetate andhexanes and once from ethyl acetate to giveZea-fluoro-17fi-hydroxy-5u-androstan- 3-one melting at 201205.5 C. Afurther recrystallization raised the melting point to 203205.5 C. andgave product having the analysis below.

Analysis.-Calcd. for C H FO C, 73.99; H, 9.48; F, 6.61. Found: C, 73.86;H, 9.66; F, 6.24.

Following the procedure of Preparation 3, but substituting astoichiometric equivalent amount of6a-anethyl-17fihydroxy-4-androsten-3-one as the starting steroid thereis thus produced 6ot-methyl 17 ,6 hydroxy-5a-androstan-3- one.

Similarly,

17fi-hydroxy-4-androstene-3,1l-dione, 2a-fluoro-178-hydroxy-4-androstene-3 ,1 l-dione,6a-me'thyl-17fi-hydroxy-4-androstene-3 1 l-dione, 11fi,17,8-dihydroxy-4-androstene-3-one, 2ot-fluoro-1 18,17B-dihydroxy-4-androsten-3-one, and fia-methyl-l1B,17B-dihydroxy-4-androsten-3-one are hydrogenated to17fi-hydroxy-5a-androstane-3, 1 l-dione,Zea-fluoro-17p3-hydroxy-5a-androstane-3,1l-dione,6a-methy1-17B-hydroxy-5 u-androstane-3,1 l-dione,1118,17/8-dihydroxy-5a-androstan-3-one, 2a-flu=oro-1113,17fi-dihydroxy-5oc-androstan-3-one, and 6a-methyl-115,17p-dil1ydroxy-5u-androstan-3-one, respectively.

PREPARATION 4 2 oz-F l u0r0-1 7,8-H yd may-5 a-A ndroutan-3 -One 1 7 -Acetate A mixture of 3 g. of Zea-fluoro-17,8-hydroxy-5a-androstan-3-one,20 ml. of dry pyridine and 15 ml. of acetic anhydride is maintained at atemperature of about 26 C. for 22 hours. The mixture is then poured into250ml. of water and stirred for 2 hours at about 26 C. The precipitated2a-fiuoro-17B-hydroxy-5a-androstan-3-one 17- acetate is separated byfiltration, Washed with water, and dried.

Similarly,

6a-methyl-17i3-hydroxy-5u-androstan-3-one, 17B-hydroxy-5u-androstane-3,1 l-dione, 2a-fiuo'ro- 1 7 B-hydr-oxy-S a-androstane-3 1 1 -dione,Ga-methyl-17 3-hydr0xy-5a-androstane-Zi,1 l-dione,11B,17B-dihydroxy-5a-androstan-3-one,2u-fluoro-11,8,17fl-d-ihydroxy-5a-androstan-3-one, and6ix-methyl-11,3,17fi-dihydroxy-5u-androstan 3 one are converted byacetylation of the 17p-hydroxy group to 6a-methyl-17Bhydroxy-5a-androstan-3-one 17-acetate, l7fl-hydroxy-5ix-androstane-3 ,1l-dione 17-acetate, 2a-fluoro-17fi-hydroxy-5a-androstane-3,1l-dione 17-acetate, 6u-methyl-17/3-hydroxy-5 u-androstane-3,11-dione 17 acetate, 11 ,B, 17,3-dihydroxy-5wandrostan-3-one 17-acetate,2a-fluoro-11,6,17,8-dihydroxy-5a-androstan-B-one 17- acetate, and6u-methy1-11B,17fi-dihydroxy-5a-androstan-3-one 17- acetate,respectively.

Similarly,

2a-fluoro-17/3-hydr0xy-5a-androstam3-one, 6a-methyl-17l8hydroxy-5a-androstan-3-one, 17 3-hydroxy-5a-androstane-3 ,1 l-dione,Za-fluoro-l7fi-hydroxy-5a-androstane-3 ,1 l-dione, 6a-methyl-17fl-hydroxy-5 u-androstane-3 ,1 1-dione,

1 1B,17fi-dihydroxy-5u-androstan-3-one,

Za-flHOIO-l 1,8,17,8-dihydroxy-5a-androstan-3-one, and 6u-methyl-11,8,17fl-dihydroxy-5a-androstan-3-one are converted to othercorresponding 17-acy1ates by esterification of the 17/8-hydroxy group,e.g., by reaction with the appropriate acid anhydride, acid chloride orbromide, acid in the presence of an esterification catalyst, etc.,wherein the acyl group is the acyl radical of, for example, a saturatedstraight-chain aliphatic acid, e.g., formic, acetic, propioni-c,'butyric, Valerie, hexanoic, lauric, a saturated branched-chainaliphatic acid, e.g., trimethylacetic, isobutyric, isovaleric, tertiarybutylacetic, a cycloaliphatic saturated acid, e.g.,B-cyclopentylpropionic, cyclohexane-carboxylic, cyclohexylacetic, analkaryl acid, e.g., benzoic, phenylacetic, fi-phenylpropionic, m,prto'luic, a saturated dibasic acid (which can be converted intowater-soluble, e.g., sodium, salts), e.g., succin-ic, adipic, amonobasic unsaturated acid, e.g., acrylic, crotonic, undecylenic,propiolic, undecolic, cinnamic, dibasic unsaturated acids (which can beconverted into watersoluble, e.g., sodium, salts), e.g., maleic andcitraconic.

EXAMPLE 1 (Reaction 1.)-2a-Flu0r0-3a,17B-DihydroxyJot-Androstane17-Acetate (110:) and Zea-F Moro-3 8,1 7,6-Dihy- .droxy-5a-Andr0stane17-Acetate (I) To 14 g. of lithium aluminum tri-t-butoxide hydridesuspended in 125 ml. of tetrahydrofuran there was added 7.0 g. rnmoles)of Zoe-fluoro-17fl-hydroxy-Sa-androstan-3-one l7-acetate at roomtemperature. The reaction mixture was stirred for three-fourths of anhour. The excess reducing agent was then destroyed by the addition of 20ml. of 3 N hydrochloric acid in 150 ml. of water. The volatile solventwas removed under reduced pressure and the acidified suspensionremaining was extracted with several portions of methylene chloride.chloride extracts were combined, washed consecutively with water, sodiumbicarbonate solution, sodium chloride solution, dried over anhydroussodium sulfate, and the methylene chloride was distilled in vacuo togive a residue. The residue was dissolved in ml. of methylene chlorideand poured ontoa 250 g. Florisil (synthetic magnesium silicate)chromatographic column packed wet with comrnercial hexanes. The columnwas developed by eluting over a gradient of from 2 to 10% acetone incommercial hexanes while collecting 25 400ml. fractions. The eluatefractions were freed of solvent. Those fractions which thin-layerchromatography showed to contain the 3mhydroxy isomer (the less polarmaterial) were combined and recrystallized from acetone to give2u-fiuoro-3a,17t3- dihydroxy-Sa-androstane 17-acetate (Ila) melting at2-09- 211" C. (with decomposition). Recrystallization of a portion ofthis material from acetone gave an analytical sample of2u-fiuoro-3a,17fi-dihydroxy-5a-androstane 17- acetate (Ha) having amelting point of 209211 C. (with decomposition), infrared absorptionbands (Nujol) at 3460, 1712 and 1265 cm? and the following analysis:

Analysis.Calcd. for C H O F: C, 71.55 H, 9.44; F, 5.34. Found: C, 71.62;H, 9.25; F, 5.36.

Those fractions which thin-layer chromatography showed to contain theSfl-hydroxy isomer were combined and recrystallized from acetone to give2u-fluoro-3fi,l7/3- dihydroxy-5a-androstane 17-acetate (Ht?) melting at166.0l67.0 C. Recrystallization of a portion of this material fromacteone gave an analytical sample of 20:-fluor-o-3p,17/8-dihydroxy-5u-androstane 17-acetate (11 3) having amelting point of 166.0-1670" C., infrared absorption bands ('Nujol) at3440,1720 and 1258 cm.- and the following analysis:

Analysis.-Calcd. for C H O F: C, 71.55 H, 9.44; F, 5.39. Found: C,71.71; H, 9.40; F, 5.28.

Similar-1y substituting a stoichiornetric equivalent amount of4u-methyl-17B-hydroxy-5u-androstan-3-one 17 acetate,

6a-methyl-17B-hydroxy-5a-androstan-3-one 17-acetate,

17 3-hydroxy-5a-androstane-3,1l-dione l7-acetate,

2m-fluoro-17fi-hydroxy-5a-androstane-3,ll-dione 17- acetate,

6a-methyl-17fl-hydroxy-5a-androstane-3,l-l-dione 17- acetate,

1118,17fi-dihydroxy-5a-androstan-3-one 17-acetate,

acetate, and 6a-methyl-1118,17 3-dihydroxy-5a-androstan-3-one 17-acetate,

The methylene for 2u-fluoro-17fl-ihydroxy-5wandrostan-3-one 17 acetateis productive of 4a-methy1-3a,17fi-dihydroxy-5u-androstane 17-acetateand 4a-methyl-35,17/3-dihydr-oxy-5a-androstane 17-acetate,

6a-methyl-3a,17fi-dihydroxy-5a-androstane 17-acetate and6a-methyl-3fi,l7,3-d-ihydroxy-5u-androstane 17-acetate,

3u,l7fi-dihydroxy-5a-androstan-1l-one 17-acetate and 38,17,B-dihydIOXy-Sa-andnoStan-1 l-one 17-acetate,

2a-fluoro-3 a,171$,dihydroxy-5a-androstan-ll-one 17- acetate and204-1111010315, l7fi-dihydroxy-5a-androstan- 1 l-one 17- acetate,

6u-methyl-3 ot,17fl-dihydroxy-5a-androstan-ll-one l7- acetate and6a-methyl-35,17(3-dihydroxy-5a-androstane-1l-one 17- acetate,

30,11B,17p-trihydroxy-Sa-andmnstane 17-acetate and 35,1 1 817fl-trihydroxy-5a-and-rostane 17-acetate,

2a-fluoro-3 ot,l15,17,8-trihydroxy-5a-androstane l7- acetate and2a-fluoro-3 5,1 1B,17fi-trihydroxy-5a-androstane 17-acetate,

and

6rx-methyl-3 (1,1 1 6,17B-trihydroxy-Sa-androstane 17- acetate and6a-methyl-3B,1 1B,l7B-trihydroxy-5u-androstane 17- acetate,respectively.

EXAMPLE 2 (Reaction 2) .-2 a-Fluo ro' 3a,] 7fi-Dihydroxy-5u-A ndrostan'e3-Dihydropyranyl Ether l 7-A cetate (III) To 1.8 g. of2a-fluoro-3a,l7/3-hydroxy-5u-androstane l7-a-cetate (Ha), obtainedaccording to the procedure of Example 1, suspended in 10 ml. ofdihydropyran and 50 ml. of ether there was added mg. ofp-toluenesulfonic acid. The ether solution was stirred overnight,extracted consecutively with sodium bicarbonate solution, saturatedsodium chloride solution, dried over anhydrous sodium sulfate and takento dryness under reduced pressure to give a light yellow crystallineresidue comprising 2aflu0r0-3oz, 17/8-dihydroxy-5u-androstane3-di'hydropyrauyl ether 17acetate (III) having infrared absorption bands(Nujol) at 1732 and 1245 cm.- This residue was used in the followingexample Without further purification.

Similarly substituting a stoichiometric equivalent amount of4a-methyl-3a,17B-dihydroxy-5u-androstane 17-acetate,

6u-methyl-3a,l75-dihydroXy-5a-androstane l7-acetate,

30a, 1 7fl-dihydroxy-Sa-andmstan-1 l-one 17-acetate,

6a-methyl-3 oz, l7fl-dihydroxy-Sa-androstan-1 l-one 17- acetate,

30:,1 15, l7fl-trihydroxy-5a-androstane 17-acetate,

2a-tluoro-3 ,1 lfi,17 3-trihydroxy-Sa-androstane 17-acetate,

and

6uc-rnethyl-3a,115,17B-trihydroxy-Sm-androstane 17 acetate, obtainedaccording to the procedure of Example 1, fo 2a-fluoro-3a,178-dihydroxy-5a-androstane 17- 136a-methyl-3a,11B,175-trihydroxy-5a-androstane 3-dihydropyranyl ether17-acetate, respectively.

EXAMPLE 3 (Reaction 3) .-2a-Fla0r0-3u,17B-Dihydr0xy-5a-Andr0- stane3-Dihyar0pyranyl Ether (IV) The light yellow crystalline residuecomprising 201- fluoro-3w17B-dihydroxy-5u-androstane 3 dihydropyranylether 17-acetate (III), obtained in Example 2, was dissolved in 100 m1.of potassium carbonate in methanol-water (4:1) solution and the reactionmixture was heated to reflux for 1 /2 hours. The solvents were removedunder reduced pressure to give 2.5 g. of a crystalline tan residuecomprising 2a-fiuoro-3a,17fi-dihydroxy- Son-androstane S-di-hydropyranylether (IV) which was used in the following example without furtherpurification.

Similarly substituting the residues comprising 4a-methyl-3vl7,8-dihydroxy-5a-androstane 3-dihydropyranyl ether l7-acetate,6u-methyl-3a,17/3-dihydroxy-5a-androstane 3-dihydropyranyl ether17-acetate,

3a,175-dihydroxy-5a-androstan-1l-one 3-dihydropyrany1 ether 17-acetate,

2a-fluoro-3e,17 S-dihydroxy-5u-androstan-1l-one 3-dihydropyranyl ether17-acetate,

6a-methyl-3a,17fi-dihydroxy-5a-androstan-1l-one 3-dihydropyranyl ether17-acetate,

3 11,1 1,6,17B-trihydroxy-5a-androstane 3-dihydropyranyl ether17-acetate,

2a-fluoro-3a,11B,17fi-trihydroxy-5u androstane 3-dihydropyranyl ether17-acetate, and

6a-methyl-3a, 1 1B,17(3-trihydroxy-5u-androstane 3-dihydropyranyl ether17-acetate, obtained according to the procedure of Example 2, for theresidue comprising Zoe-fiLlOI'O-3 m, 1 7 ot-dihydroxy-Su-androstane3-dihydropyranyl ether 17-acetate is productive of residues comprising4a-methyl-3a,17,8-dihydroxy-5a-androstane 3-dihydro pyranyl ether,

6a-methyl-3a,17fl-dihydroxy-Sa-androstane 3-dihydropyranyl ether, l

3 a, 17 fi-dihydroxy-S a-androstan- 1 l-one 3-dihydropyranyl ether,

2a-fil1OIO-3u, 17 Bdihydroxy-S a-androstan-l l-one 3-dihydropyranylether,

6a-methyl-3a,17B-dihydroxy-5-a-androstan-1l-one 3-dihydropyranyl ether,

3 a1 1 B, 17 B-trihydroxy-S a-androstane 3-dihydropyranyl ether,

2u-fluoro-3u,11B,17fi-trihydroxy-5a-androstane '3 -dihydro pyranylether, and

6u-methyl-3a,l 1 B, 17 B-trihydroxy-S a-androstane 3-dihydropyranylether, respectively.

EXAMPLE 4 (Reaction 4) .2 a-Flaorou-Hya'rOxy-Sa-A ndrostan-J 7- One3-Dihydropyranyl Ether (V) The 2.5 g. of crystalline tan solidcomprising 2a-fluoro- 3a,l7B-dihydroxy-5a-androstane 3-dihydropyranylether (IV), obtained in Example 3, was taken up in 10 ml. of pyridineand added to a pyridine-chromic acid complex prepared from 2 g. ofchromic anhydride in 20 ml. of pyridine. The reaction mixture Wasstirred for five hours at room temperature, diluted with ether-benzene(1:1) and filtered on a Celite (diatomaceous earth) pad. The filtratewas washed consecutively with water and saturated sodium chloridesolution, dried over anhydrous sodium sulfate and taken to dryness underreduced pressure and the residual pyridine was distilled azeotropicallywith toluene under reduced pressure to yield a light brown residuecomprising 2ot-fiuoro-3a-hydroxy-5u-androstan-17- one S-dihydropyranylether (V) which was used in the following example without furtherpurification.

Similarly substituting the residues comprising 4a-methyl 3 a,178-dihydroxy-5a-androstane 3-dihydropyranyl ether,

6a-methyl-3a,17fl-dihydroxy-5a-androstan 3-dihydropyranyl ether,

3a,l7,8-dihydroxy-Sea-androstan-1l-one 3-dihydropyranyl ether,

2a-fluoro-3a,1713-dihydroxy-5a-androstan-1l-one 3-dihydropyranyl ether,and

6a-methyl-3a, l7B-dihydroxy-5a-androstan-1 l-one 3-dihydropyranyl ether,obtained according to the procedure of Example 3, for the residuecomprising Za-fiuoro-Bu,17 8-dihydroxy-5a-androstane 3-di-hydropyranylether is productive of residues comp-rising4a-methyl-3a-hydroxy-5a-androstan-17-one 3-dihydropyranyl ether,

6a-methyl-3ot-hydroxy-5a-androstan-17-one 3-dihydropyranyl ether,

3a-hydrQXy-Su-androstane-11,17-dione 3-dihydropyrany1 ether,

2a-fluoro-3 a-hydroxy-Sa-androstane-11,17-dione 3-dihydropyranyl ether,and

6a-methyl-3a-hydroxy-5 a-androstane- 1 1, 17-di0ne 3 -dihydropyranylether, respectively.

EXAMPLE 5 (Reaction 5 .2 a-Fluor0-3 a-HydrOxy-Sa-A ndrostan-I 7- One (VIThe light brown residue comprising2a-fiuoro-3a-hydroxy-Sa-andmstan-17-0ne B-dihydropyranyl ether (V),obtained in Example 4, was taken up in 20 ml. of acetone and 2 ml. of 3N hydrochloric acid was added thereto. The reaction mixture, afterstanding at room temperature overnight, yielded a first crop ofcolorless crystals weighing 440 mg. and having a melting point of217217.5 C. (with decomposition). Dilution of the filtrate with Wateryielded a second crop of colorless crystals Weighing 630 mg. and havinga melting point of 215215.5 C. (with decomposition). The first andsecond crops were combined and a portion recrystallized from acetone toyield an analytical sample of 2a-fiuoro-3a-hydrOXy-Sa-androstan-17-one(VI) having a, melting point of 219-219.5 C. (with decomposition),infra-red absorption bands (Nujol) at 3480 and 1725 crrL- and thefollowing analysis:

Analysis.Calcd. for C H O F: C, 74.22; H, 9.18; F, 6.18. Found: C,73.91; H, 9.27; F, 6.13.

Similarly substituting the residues comprising4a-methyl-3a-hydroxy-5a-androstan-l7-one 3-dihydropyranyl ether,

6a-methyl-3 a-hydrOXy-Sa-androstan-17-one 3-dihydr0- pyranyl ether,

3a-hydroxy-5u-androstane-11,17-dione 3-dihydropyranyl ether,

2a-fiuoro-3 a-hydroxy-Sa-androstane-11,17-di0ne 3 -dihydropyranyl ether,and

6u-methyl3a-hydroxy-5u-androstane-11,17-dione 3 dihydropy-ranyl ether,obtained according to the procedure of Example 4, for the residuecomprising 2a-fluoro-3ahydroxy-5a-androstan-17-0ne 3-dihydropyranylether is productive of 4a-methyl-3 a-hydroXy-Sa-andmstan-17-one,

6a-methyl-3a-hydroxy-5a-androstan-17-one,

3 a-hydroxy-5a-androstane-l 1,17-dione,

6a-methyl-3a-hydroxy-5a-androstane-11,17-dione, respectively.

EXAMPLE 6 (Reaction 6) .2 a-Flu0r0-3a-Hydr0xy-5a-A ndrostane-11,17-Di0ne 17-Ethylene Ketal (VII) 1 g. of2a-fiuoro-3a-hydroXy-Sa-andmstane-l1,17-dione (VI), obtained accordingto the procedure of Example 5, is dissolved in a mixture of 50 ml. ofbenzene and 5 ml. of ethylene glycol containing mg. of p-toluenesulfonicacid. The reaction mixture is refluxed overnight, during 2a-fluoro-3a-hydroxy-a-androstane-1 1,17-dione 17-ethylene ketal (VII) which'isused in the following example without further purification.

Similarly amount of substituting a stoichiometric equivalent2a-fiuoro-3a-hydroxy-5u-androstan-17-one,

4ot-methyl-3m-hydmXY-Sa-androstan-17one,

6a methyl-3 a-hydroxy-5u-androstan-17-one,

3u-hydroxy-5ot-androstane-1 1,17-dione, and

6oz-methyl-3ix-hydroxy-5a androstane 11,17 dione, obtained according tothe procedure of Example 5, for2afluoro-3a-hydroxy-5a-androstane-11,17-dione is productive of residuescomprising 2ot-fluoro-3a-hydroxy-5ot-androstan-17-one 17-ethylene ketal,

4u-methyl-3u-hydroxy-5m-androstan-17-one 17-ethylene ketal,

6a-methyl-3a-hydroxy-5a-androstan-17-one 17-ethylene ketal,

3u-hydroxy-5u-androstane-l l,17dione 17-ethylene ketal,

and

6et-methyl3a-hydroxy-5u-androstane-11,17-dione 17- ethylene ketal,respectively.

EXAMPLE 7 (Reaction 7) .2a-Flworo-3u,l15-Dihydr0xy-5a-Andr0- stun-17-0ne 17-Ethylene Ketal (VIII) The residue comprising2a-fluoro-3whydmxy-Sa-androstane-11,17-dione 17-ethylene ketal (VII),obtained in Example 6, is added to a solution of 100 mg. of lithiumaluminum hydride in 25 ml. of tetrahydrofuran and the reaction isallowed to proceed at reflux for one hour. The reaction mixture ischilled and the excess lithium aluminum hydride is destroyed by theaddition of 1 ml. of ethyl acetate, followed by 0.5 ml. of water. Thethus obtained mixture is then filtered and the filtrate taken to drynessunder reduced pressure to yield a residue comprisingZoc-fiIJOI'O-3ot,l1fi-dihYdIOXY-Sct-filld-IOSHIII-17 one 17-ethyleneketal (VIII) which is used in the following example without furtherpurification.

Similarly substituting the residues comprising3u-hydroxy-5a-androstane-11,17-dione 17-ethylene ketal,

and 6a-methyl-3tx-hydroxy-5tz-androstane-11,17-dione 17-eth ylene ketal,obtained according to the procedure of EX- ample 6, for the residuecomprising 2u-fiuoro-3a-hydroxy-5a-androstane-11,17-dione is productiveof residues comprising 311,11,6-dihydroxy-5a-androstan-17-one17-ethylene ketal,

and 6a-methyl-3a, 1 1[3-dihydroxy-5ot-androstan-17-one 17-ethyleneketal, respectively.

EXAMPLE 8 (Reaction 8) .-2a-Flu0r0-3u,1l'fi-DihydrOxy-Sa-Androstan-17-One (IX) 4% sodium bicarbonate until crystallization takesplace.

The crystalline material comprising2ot-fi-uoro-3a,11B-dihydr-QXy-Sa-androStan-l7-one is isolated, washedthoroughly with water and taken up in methylene chloride. The thusobtained methylene chloride solution is poured onto a 75 g. Florisilchromatographic column packed wet with commercial hexanes. The column isdeveloped by eluting over a gradient of from 5 to 20% acetone incommercial hexanes while collecting IOO-ml. fractions. The eluatefractions are freed of solvent. Those fractions which thin-layerchromatography show to contain the desired product are combined andrecrystallized from alcohol-water to yield2a-fiuoro-3a,11B-dihydroxy-5a-androstan-17-one (IX).

- Similarly substituting the residues comprising30L,1Ifi-dihYdIOXY-Sot-BHGIOSIIHH-17-0118 17-ethylene ketal,

and

6a-methyl-3u,11B-dihydroxy-5a-androstan-17-one l7-ethylene ketal,obtained according to the procedure of Example 7, for the residuecomprising 2oz-flL10f-O-3 11,1 1fl-dihydroxy-M-androstan-17-one17-ethylene ketal is productive of 301,11;8-dihydroxy-5ot-androstanl7-one, and

6a-methyl-3 oz, 1 1,8-dihydroxy-5 a-androstan- 17-one, respec tively.

EXAMPLE 9 (Reaction 9) .-2 Flume-3 3,1 7;8-Dilzydroxy-5a-A ndrostane3-p-Tosylwte 17-Acetate (X) To 1.83 g. of2a-fluoro-3fi,17B-dihydroxy-5a-androstane 17-acetate (II/9), obtainedaccording to the procedure of Example 1, dissolved in 15 ml. of pyridinethere was added 1.83 g. of p-toluenesulfonyl chloride. The reaction mixture was allowed to stand at room temperature overnight, following whichthe solution was poured into 250 ml. of 3 N hydrochloric acid and cooledat 4 C. for 10 hours during which time a precipitate formed. Thesupernatant liquid was decanted from the precipitate and the latter wasdissolved in 50 ml. of methylene chloride. The thus obtained solutionwas washed consecutively with dilute hydrochloric acid and saturatedsodium chloride solution, dried over anhydrous sodium sulfate and takento dryness under reduced pressure to give a residue which wasrecrystallized from methanol in two crops. The two crops were combinedto give 1.8 g. of 2m-fluoro-3fi,17 B-dihydroxy-5a-androstane3-p-tosylate 17-acetate (X) having a melting point of 133134.5 C. Aportion was recrystallized twice from methanol to yield an analyticalsample of Za-fluQro-Bn,17,8-dihydroxy-5a-androstane 3-p-tosylate17-acetate having a melting point of 1365-1375 C., inflared absorptionbands (Nujol) at 1740, 1601, 1494 and 1315 cm." and the followinganalysis:

Analysis.-Calcd. for C H O SF: C, 66.37; H, 7.75; S, 6.32; F, 3.74.Found: C, 66.16; H, 8.03; S, 6.30; F, 3.48.

Similarly substituting a stoichiometric equivalent amountof4a-methy1-3B,l7 8-dihydroxy-5a-androstane 17 -acetate,6utmethyl-3;3,17fl-dihydroxy-Sa-androstane 17-acetate,3,8,17B-dihydroxy-5a-androstan-ll-one 17-acetate,2a-fluoro-3p,17,6-dihydroxy-5a-androstan-l l-one 17- acetate,6a-methyl-3p,l7fi dihydroxy-5a-androstan-1l-one 17- acetate,313,11,8,17fl-trihydroxy-5a-androstane l7-acetate, 206-fiIlOIO-3j8,1 18,17,8-trihydroxy-5a-androstane l7- acetate, and6a-methyl3fi,11,8,17,8-trihydroxy-5a-androstane 17 acetate, obtainedaccording to the procedure of'Example l, for2a-fluor-o-3p,17,8-dihydroxy-5a-androstane 17-acetate is productive of4mmethyl-3,8,17 B-dihydroxy-5u-androstane 3-p-tosylate 17-acetate,6a-methyl-3fi,17 3 dihydroxy-5a-androstane 3-p-tosylate 17-acetate,3,8,17q3-dihydroxy-5a-androstan-1l-one 3-p-t0sylate 17- acetate,

tosylate .l7-acetate,

17 6a-methyl-3B,17B-dihydroxy-5m-androstan-1l-one 3-ptosylate17-acetate, 3,3,11,8,17,8-trihydroxy-5a-androstane 3-p-tosylate 17-acetate, 2ot-fluoro-3/3,11B,17fi-trihydroxy-5a-androstane 3-ptosylate17-acetate, and 6a-methyl-3;8,11/8,17/3-trihydroxy-5a-androstane3-ptosylate 17-acetate, respectively.

EXAMPLE 10 (Reaction 1 .2 a-F lu0r0-3 5,1 7 B-Dihydroxy-S a-A ndrastane3-p-T0sylate (XI) To 1.52 g. of2a-fluoro-318,17fi-dihydroxy-5uandrostane 3-ip-tosylate 17-acetate (X),obtained in Example 9, dissolved in 50 ml. of warm methanol there wasadded 1 ml. of concentrated hydrochloric acid. The reaction mixture wasallowed to come to room temperature overnight, diluted with 50 ml. ofwater, followed by removal of the alcohol under reduced pressure toyield a residue. The residue was extracted with several portions ofether and the combined ether extracts were washed consecutively withwater and saturated sodium chloride solution, dried over anhydroussodium sulfate and taken to dryness under reduced pressure to give acolorless glass residue comprising2a-fiuoro-3fi,17,8-di-hydroxy-5wandrostan'e 3-p-t0sylate (XI). A portionof the glass was recrystallized from methanol to yield2a-fiuor0-3B,17B-dihydroxy-a-androstane 3-p-tosylate having a meltingpoint of 93.5-100 C.

Similarly substituting a stoichiometric equivalent amount of4amethyl-3,B,17,13-dihydroxy-5a-androstane 3-p-tosylate 17-acetate,

6a-1'1'1611I1Yl-3 8, 17,8-dihydroxy-5 u-androstane 3-p-tosylate17-acetate,

3 B,17B-dihydroxy-5u-androstan-1 l-one 3-p-tosylate 17-acetate,

2a-fluoro-3 13,17,8-dihydroxy-5 a-androstaml l-one 3-ptosylate17-acetate,

6u-methyl-313,175-dihydroxy-5a-and rostan-1 l-one 3 ptosylate17-acetate,

3 5, 1 113, 17fi-trihydroxy-5wandrostane 3 -p-tosylate 17- acetate,

2u-fluoro-3 [3,1 118,17B-trihydroxy-Sa-androstane 3-ptosylate17-acetate, and

6-methyl-3B,115,17B-trihydroxy-5a-androstane 3-ptosylate 17-acetate,obtained according to the procedure of Example 9, for2a-fluoro-3f3,l7fi-dihydroxy 5a-androtsane-3-p-tosylate 17-acetate, isproductive of residues comprising4a-methyl-3fl,17B-dihydroxy-5oc-androstane 3-p-tosylate,

6a-methy1-3B,17B-dihydroxy-5a-androstane 3-p-tosylate,

3 6,17B-dihydroxy-5a-androst-an-1 l-one 3 -p-tosylate,

2a-fluoro-3fl,17,8-dihydroxy-5a-androstan-1l-one 3-ptosylate,

6a-methyl-313,17,8-dihydroxy-5a-androstan-1l-one 3 -ptosylate,

3 B, 1 1 8, l7B-trihydroxy-Swandrostane 3-p-tosylate,

2oc-flI10I0-3 5,11 5,17 ,B-trihydroxy-S a-androstane 3-ptosylate, and

6u-me-thyl-3 6,1 1 8,17,8-trihydroxy-5u-androstane 3-ptosylate,respectively.

EXAMPLE 11 (Reaction 1] .2u-Fluoro-3fl-Hydroxy-5a-Androstan-I 7- one 3-p-Tosylate (XII) The glass comprising 2 xfluoro-3;3,17fi-dihydroxy-5a-:androstane 3-p-tosylate (XI), obtained in Example 10, was taken up in15 ml. of pyridine and added to a pyridine-chromic acid complex preparedfrom 1.5 g. of chromic anhydride in 15 ml. of pyridine. The reactionmixture was stirred for 5 hours :at room temperature, diluted withether-benzene (1:1) and filtered on a Celite pad. The filtrate wasWashed consecutive-1y with water and saturated sodium chloride solution,dried over anhydrous sodium sulfate and taken to dryness under reducedpressure and the residual pyridine was distilled azeotropically withtoluene under reduced pressure to yield a white crystalline solid whichupon recrystallization from methanol yielded 1.1 g. of2ot-fluoro-3fl-hydroxy-5a-androstan- 17-one 3-p-tosylate (XII) having amelting point of 201- 202.5 C. A portion was again recrystallized frommethanol to yield an analytical sample of2a-fluoro-3B-hydroxy-5ot-androstan-17-one 3-p-tosylate having a meltingpoint of 202203.5 C., infrared absorption bands (Nujol) at 1730, 1596,1491 and 1359 cm.- and the following analysis:

Analysis.Ca-lcd. for C H O FS: C, 67.50; H, 7.63; S, 6.93. Found: C,67.82; H, 7.90; S, 7.26.

Similarly substituting the residues comprising4a-methyl-3B,17B-dihydroxy-Sa-andrOstane 3-p-tosylate,

6a-methyl3,8,17,6-dihydroxy-5a-androstane 3-p-tosylate,

3 B,17B-dihydroxy-5a-androstan-1 l-one-S-p-tosylate,

2a-fluoro-3B,17fi-dihydroxy-5a-androstan-1l-one 3-ptosylate, and

6a-methyl-3fl,17B-di-hydroxy 50c androstan-ll-one 3-p tosylate, obtainedaccording to the procedure of Example 10, for the residue comprising2oc-flUOIO-3fi,17B-dihydroxy-5u-androstane 3-p-tosylate is productive of4a-methyl-35-hydroxy-5ot-androstan-17-one 3-p-tosylate,

6a-methyl-3/3-hydroxy-5a-andr0stan-17-one 3 -p-tosylate,

3fl-hydroxy-Sa-androstane-11,17-dione 3-p-tosylate,

2afiuoro-3[3-hydroxy-5a-androstane-11,17-dione 3-ptosylate, and

6a-methyl-3 ,8-hydroxy-5a-androstane-11,17-di0ne 3 -ptosylate,respectively.

ExAMPLE 12 (Reaction 12 .2-Flu0ro-5a-Androst-2-en-17- one (XIII) and2a-Flu0r0-3a-Hydr0xyJa-Androstun-I 7-One 3- Formate (XIV) 0.96 g. of2a-fluoro-35-hydroxy-5wandr0stan-17-one 3-p-tosylate, obtained inExample 11, in 25 ml. of dimethylforrnamide containing 1.0 g. of sodiumformate was placed in a sealed tube and heated to 220 C. overnight.Following the cooling of the sealed tube to room temperature it wasopened and the reaction mixture contained therein poured into 300 ml. ofwater to give a solid and a liquid phase. The solid phase was collectedon a funnel, washed with water and dried in vacuo at 60 C. to yield aresidue comprising 2-fluoro-5u-androst-2-en-17- one (XIII) and2a-fluoro-3a-hydr0xy-5a-and-rostan-17- one 3-formate (XIV) which wasused in the following example without further purification.

Similarly substituting a stoichiometric amount of equivalent4OL-II16thYl-3 ,B-hydroxy-S a-androstan-17-one 3-p-tosylate,6a-methy1-3p-hydroxy-5u-androstan-17-one 3-p-tosylate,3B-hydroxy-Sa-androstant-l1,17-dione 3-p-tosylate,2oi-fluoro-3fi-hydroxy-h-androstane-11,17-di0ne 3-pt-osylate, and6u-methyl-3B-hydroxy-Sa-androstane 11,17 dione 3 ptosylate, obtainedaccording to the procedure of EX- ample 11, for2a-fluoro-3B-hydroxy-Sa-andmstan-17- one 3-tosylate is productive ofresidues comprising 4oc-methyl-5zx-ar1drost-2-en- 17-one and4a-methyl-3a-hydroxy-5a-androstan-17-or1e 3-formate,6a-methyl-5a-androst-2-en-17-one and6a-methyl-3a-hydroxy-5a-androstan-17-one 3-formate, 5a-ar1drost-2-ene-l1,17-dione and 3a-hydroxy-5u-androstane-1 1,17-dione 3-formate,2a-fluoro-5u-androst-2-ene-11,17-di0ne and2ot-fluoro-3u-hydroxy-5a-androstane-11,17-dione 3- formate, and6a-methyl-Sa-androst-Z-ene-11,17-dione and6a-methyl-3a-hydroxy-5u-androstane-1 1, 17-dione 3- formate,respectively.

(Reaction 13) .2-FlZlOrO-50L-A ndrost-Z-en-I 7-0ne (XIII) and2a-Fluoro-3ot-Hydroxy-5u-A ndrostan-I 7-0n'e- (VI The residue comprising2-fll10IO-5a-a11dl0St-2-61'1-17- one (XIII) and2oc-flU010-3cc-hYdIOXy-Sa-al'ldfOSt3Il-17- one 3-formate (XIV), obtainedin Example 12, was dissolved in benzene and poured onto a 100 g. FisherA-540 alumina chromatographic column made up with benzene. The columnwas developed by eluting over a gradient of to methanol in benzeneduring 30 50- ml. fractions. The eluate fractions were freed of solvent.Those fractions which thin-layer chromatography showed to contain the3a-hydroxy compound were combined to give 523 mg. of solid materialwhich upon recrystallization from acetone yielded 280 mg. of2a-fluoro-3u-hydrOXy-Sa-androStan-l7-one (VI) having a melting point of210-214 C. (with decomposition). The thus obtained2u-fiuoro-3u-hydroxy-5a-androstan-17-one had an infrared analysis whichwas identical with that obtained for the product of Example 5 and didnot depress the melting point on admixture with the product obtained inExample 5.

Those fractions which thin-layer chromatography show to contain the Acompound are combined and recrystallized from alcohol-water to yieldZ-flllOlO-Soc-Hl'ldfOSt-Z- en-17-one.

Similarly substituting the residues comprising4a-rnethyl-Sa-androst-Z-en-17-one and4a-methyl-3a-hydroxy-5u-androstan-17-one 3-formate,6a-methyl-Sa-androSt-Z-en-17-one and6u-methyl-3m-hydroxy-5rx-androstan-17-one 3-formate,Sa-androst-Z-ene-l1,17-dione and 3 a-hydroXy-Sa-andrOStane-I1,17-dione3-formate, Za-fluoro-Sa-androst-2-ene-l1,17adione and2a-fiuoro-3a-hydroxy-5u-androstane-l1,17-dione 3- formate, and6a-methyl-5ot-androst-2-ene-11,17-dione and6a-methyl-3u-hydrOXy-Sa-androstane-I1,17 dione 3 formate, obtainedaccording to the procedure of Example 12, for the residue comprising2a-fiuoro-5a-androst-2- en-17-one and2a-fluoro-3a-hydroxy-Sa-andmstan-17- one 3-formate is productive of4a-methyl-5a-androst-Z-en-l7-one and4a-methyl-3a-hydroxy-5a-androstan-17-0ne,6a-methyl-5u-androst-2-en-l7-one and6oc-n1ethyl-3a-hydroxy-5a-androstan-17-one, Sa-androst-Z-ene-l1,17-dione and 3a-hydroxy-5m-androstane-11,1'7-dione,ZOL-fiUOl'O-SOL3I'ldI'OSi.-2-6l1-11,17-dl0n6 and 2oc-fi110rO-3u-hydrOXy-Sa-andmstane-11,17-dione, and 6a-methyl-5a-androSt-Lene-11,17-dione and 6a-methyl-3a-hydroxy-5ot-androstane-11,17-dione(respectively.

EXAMPLE 14 (Reaction 1 4 .2u-Flu0r0-3a,1 7B-Dihydr0xy-5a Androstane (XVet) 70 mg. of 2|x-fluoro-311,175-dihydroxy-5u-androstane 17-acetate(Ila), obtained according to the procedure of Example 1, was dissolvedwith warming in 3 ml. of 5% potassium hydroxide in methanol, followed bythe addition of three drops of water. After standing overnight at roomtemperature the solution was warmed on a steam bath and diluted toincipient crystallization by the dropwise addition of water. Uponcooling colorless prisms crystallized and they were isolated byfiltration and air dried to give 49.0 mg. of2ot-fluoro-3a,l75-dihydroxy-5aandrostane (XVu) having a melting point of209.5- 211.0 C. Recrystallization of a portion of this material fromalcohol-Water gave an analytical sample of2afluoro-3a,17/3-dihydroxy-5u-androstane having a melting point of209.5-211 C., infrared absorption bands (Nujol) at 3510, 3390', 1135,1080, 1045 and 1025 cm. and the following analysis:

20 Analysis.Calcd. for C H O F: F, 6.12. Found: F, 6.15.

Similarly amount of 4a-methyl-3a,17 8-dihydroxy-5a-androstane17-acet-ate, 6a-methyl-3a,17 8-dihydroxy-5u-androstane l7-acetate,3a,17fi-dihydroxy-5a-androstan-l l-one 17-acetate, 20t-fll1OIO-30t,17,8-dihydroxy-Sa-androstan-1 l-one l7- acetate,6a-methyl-3a,17B-dihydroxy-5a-androstan-1 l-one 17- acetate, 3a,11B,176-trihydroxy-5a-androstane 17-acetate, 2a-flLlOIO-3oc, 1 1 8,178-trihydroxy-Sat-androstane 17-acetate, and6u-methyl-3a,l1B,17,8-trihydroxy-5a androstane 17 acetate, obtainedaccording to the procedure of Example 1, for2oz-fiuoro-3or,l7,8-dihydr0xy-Six-androstane 17- acetate is productiveof 4 x-methyl-3a,17fi-dihydroxy-5tat-androstane, 6a-methyl-317fi-dihydroxy-5 a-androstane, 3 or,17,3-dihydroxy-5ot-androstan-11-one, 2a-fluoro-3u, 17B-dihydroxy-5u-androstan-1 l-one, 6a-methyl-3a,1713-dihydroxy-5ot-androstan-1l-one, 30 ,11/3,17fi3-trihydroxy-5a-androstane, 2u-fluoro-3 a,11B,17fi-trihydroxy-Soc-androstane, and6u-mflthYl-3og11,8,17,3-t1ihyd101ty-5o: androstane, respectively.

substituting a stoichiometric equivalent EXAMPLE 15 (Reaction 14).2-Fluor0-3p,I 75-Dz'hydroxy-5a- Androstcme (X VB) 60 mg. of2a-fluoro-3/3,17,8-dihydroxy-Soc-androstane 17-acetate (I15), obtainedaccording to the procedure of Example 1, was dissolved with warming in1.5 ml. of 5% potassium hydroxide in methanol, followed by the additionof a drop of water. After standing overnight at room temperature thesolution was warmed on a steam bath and diluted to incipientcrystallization by the dropwise addition of water. Upon coolingcolorless prisms crystallized and they were isolated by filtration andair dried to give 40.0 mg. of 2a-fluoro-35 17,8-dihydroxy-5aandrostanehaving a melting point of 175..0176.0 C., infrared absorption bands at3470, 3180, 1075 and 1050 cm.- and the following analysis:

Analysis.Calcd. for C I-1 0 1 F, 6.12. Found: F, 5.97.

Similarly substituting a amount of stoichiometric equivalent4a-methy1-3B,17,8-dihydroxy-5a-androstane 17-acetate,

6a-methyl-3B,17B-dihydroxy-5a-androstane 17-acetate,

3,8,17;3-dihydroXy-5a-androstan-1 l-one 17-acetate,

2a-fluoro-3 3,17,13-dihydroxy-Son-androstan-1 l-one 17- acetate,

6a-methyl-3fi,1718-dihydroxy-5a-androstan-1l-one 17- acetate,

313, 1 1,8, 17,8-trihydroxy-Set-androstane 17-acetate,

2oc-fil10I0-3 5,1 1B,1713-trihydroxy-Six-androstane 17- acetate, and

6a-methy1-3 B, 1 1B, 17,8-t1ihydroxy-5a-androstane 17-acetate, obtainedaccording to theprocedure of Example 1, for2a-fluoro-3'B,17a-dihydroxy-5a-androstane 17-acetate is productive of4a-methyl-3B,17,8-dihydroxy-Sat-androstane,

6a-methyl-3fi, 17B-dihydroxy-5a-androstane,

3 ,6, 17fi-dihydroxy-5 a-androstan-l l-one,

6a-methyl-3 3, 17 B-dihydroxy-S a-androstan-l l-one,

313,1 1B,17,6-trihydroxy-5cit-androstane,

Zen-1111010613,]. 113, -:rihydroxy-5a-androstane, and

21 EXAMPLE 16 (Reaction 12 .5oc-A ndrost-Z-Ene-I 1,1 7-Dz'0ne (XIII) and3 oc-H ydroxy-5 oc-A ndrostane-I I ,1 7 -Dine 3 -F ormate (XIV) 1.0 g.of 3B-hydroXy-Sa-andmstane-11,17-dione 3-ptosylate (XII), obtainedacocrding to the procedure of Example 11, was dissolved in 85 ml. ofdimethylformamide and the reaction mixture was heated to 80-85 C. forapproximately 120 hours. The reaction mixture was poured into 500 ml. ofsaturated sodium chloride solution and extracted with 3 l00-ml. portionsof methylene chloride. The methylene chloride extracts were combined andwashed consecutively with water (twice) and saturated sodium chloridesolution, dried over anhydrous sodium sulfate and taken to dryness underreduced pressure to give a residue comprisinga-androst-2-ene-l1,17-dione (XIII) and3a-hydroxy-5a-androstane-11,17-dione 3-formate (XIV) which was used inthe following example without further purification.

EXAMPLE 17 (Reaction I3) .5u-A ndrostat-Z-Ene-I 1 ,1 7-D ione (XIII) and3 a-H ydr0xy-5 a-Androstane-I I ,1 7 -Dione (VI The residue comprising-5a-androst-2-ene-11,17-dione (XIII) and3a-hydrOXy-Sa-andrQstane-I1,17-dione 3-formate (XIV), obtained inExample 16, was dissolved in benzene and poured onto 21.50 g. FisherA-540 alumina chromatographic column. The column was developed byeluting over a gradient of 0 to 5% benzene in methanol while collecting26 30-ml. fractions. The eluate fractions were freed of solvent. Thosefractions which thin-layer chromatography showed to contain the A2compound were combined (3 mg.) to give 5ix-androst-2-ene-11,17-dionehaving infrared absorption bands (Nujol) at 1745, 1705 and 1650 cmf Aportion was recrystallized from acetone to give an analytical sample ofSa-androst-Z-ene- 11,17-di0ne having a melting point of 192-1945 C.

Those fractions which thin-layer chromatography showed to principallycontain the 3a-hydroxy compound were combined, dissolved in 20 ml. ofmethylene chloride and poured onto a 50 g. Florisil chromatographiccolumn packed wet in commercial hexanes. The column was developed byeluting over a gradient of from 5 to 15% acetone in commercial hexaneswhile collecting 20 50-ml. fractions. The eluate fractions were freed ofsolvent. Those fractions which thin-layer chromatography showed tocontain the 3a-hydroxy compound were combined and recrystallized fromacetone-commercial hexanes to give 500 mg. of3a-hydroxy-5a-androstane-l1,17-dione (VI) melitng at 133155 C. Fourrecrystallizations of a portion of this material from acetone-commercialhexanes gave an analytical sample of needles of3oc-hYd1OXY-5ocandrostane-ll,17-dione having a melting point of 151.5-155.5 C., infrared absorption bands (Nujol) at 3470, 1730, and 1705 cm?and the following analysis:

Analysis.-Calcd. for C H O C, 74.96; H, 9.27. Found: C, 74.68; H, 9.33.

EXAMPLE 18 (Reaction 6.) 3u-Hydroxy-5a-Andr0stane-11,I 7-Di0ne17-Ethylene Ketal (VII 2.38 g. of 3u-hydroXy-5u-androstane-11,17-dione(VI), obtained acording to the procedure of Example 18, was dissolved ina mixture of 50 ml. of benzene and 10 ml. of ethylene glycol containing10 mg. of p-toluenesulfonic acid. The reaction mixture was heated torelux overnight, during which time 0.6 ml. of water collected in thewater trap. The reaction mixture was cooled, washed consecutively withwater, 4% sodium bicarbonate solution and saturated sodium chloridesolution, dried over sodium sulfate and taken to dryness under reducedpressure to give a residue comprising3a-hydroxy-5u-androstane-l1,l7-dione 17-ethylene ketal (VII) which wasused in the following example without further purification.

EXAMPLE 19 (Reaction 7). 3 a,1 I B-DihydrOxy-Sa-Andr0stan-1 7 -One 1 7-Ethylene Ketal (VIII) A The residue comprising3a-hydroxy-5a-androstane- 11,17-dione 17-ethylene ketal (VII), obtainedin Example 18, was introduced into a solution of 200 mg. of lithiumaluminum hydride in 25 ml. of ether and the reaction was allowed toproceed at reflux for 2 hours. The reaction mixture was chilled and theexcess lithium aluminum hy-.

dride was destroyed by the addition of 5 ml. of ethyl acetate, followedby 2 ml. of water. The thus-obtained mixture was then filtered and thefiltrate taken to dryness under reduced pressure to yield a residuecomprising 30c, l1 3-dihydroxy-5a-androstan-17-one l7-ethylene ketal(VIII) which was used in the following example without furtherpurification.

EXAMPLE 20 (Reaction 8). 3u,I1,8-Dihydroxy-5a-Androstan-I 7-One Theresidue comprising 30:,11B-dihydroxy-Su-androstan- 17-one 17-ethyleneketal (VIII), obtained in Example 19, was dissolved in 10 ml. of aceticacid to which was added 5 ml. of water. The reaction mixture, afterstanding overnight at room temperature, was diluted with 500 ml. of 4%sodium bicarbonate solution whereupon crystallization took place. Thecrystalline material was isolated, washed thoroughly with water andtaken up in methylene chloride. The thus obtained methylene chloridesolution was poured onto a 75 g. Florisil column packed wet withcommercial hexanes. The column was developed by eluting over a gradientof from 5 to 20% acetone in commercial hexanes while collecting 24 -ml.fractions. The eluate fractions were freed of solvent. Those fractionswhich thin-layer chromatography showed to contain the desired productwere combined and recrystallized from acetone to give a first crop of3a,11/3-dihydroxy-5a-androstan-17-one weighing 1.453 g. and melting at189-192 C. and a second crop of 3u,l1fl-dihydroxy-Sa-andmstan-l7- oneweighing 111 mg. and melting at 190192.5 C.

Four recrystallizations of the second crop from acetone.

i R1-- R o-- i f 0- wherein R is hydrogen and R is selected from thegroup consisting of hydrogen and methyl, with the proviso that and 23 24at least one but not 'both of R and R are hydrogen; X and is selectedfrom the group consisting of o l OH Y OH2, O=O and I i H R1 0 Y isselected from the group consisting of CH and li C=O; and Z is selectedfrom the group consisting of it i I'm wherein R is hydrogen and R ismethyl, Y is selected and 0 from the group consisting of CH and 0 0, andTos is the tosyl radical.

9. 2oz -fluoro-3B hydroxyfia androstan-l7-one 3-p- Wherein Ac is theacyl radical of a hydrocarbon carboxylic tosylate acid containing from 1to 12 carbon atoms, inclusive. 10, Compgunds of th f ula 7. Compounds ofthe formulae 11 k r 15 xg/ UOC S TM; 1

o H I O: /Z1 1 i i d HCO-- Tos0 an O I I I O 0-- o-- I H 5 H i 3 2 H cm()H; and

0 H wherein X is selected from the group consisting of 1 0H C=O and 0 H(JO-- t and Z is selected from the group consisting of 5 3 HO H A00 Ewherein Tos is the tosyl radical.

\ 11. 5a-androst-2-ene-11,17-dione. /C\ and /C\ 5 5 References Cited bythe Examiner wherein Ac is the acyl radical of a hydrocarbon carboxylicUNITED STATES PATENTS acid containing from 1 to 12 carbon atoms,inclusive. 3,009,934- 11/ 196 1 Counsel et a1. 260-397.4 8. Compounds ofthe formulae 3,055,916 9/1962 Bowers et al. 260-3973 3,104,244- 9/1963Counsel et a1 260-3973 0 0 3,169,136 2/1965 Bowers et a1. 260-3973 5| 1|OTHER REFERENCES Fieser et al.; Steroids (1959), Reinhold Publishing 1 iCo., pages 405, 505, 506-, 519, and 533 relied on. Journal ClinicalEndocrinol, Metab, vol. 22 (1962),

* pages 1090-1094 relied on. CA-vol. 58, 11, 785(c). Tos o I I LEWISGOTTS, Primary Examiner.

a a ELBERT L, ROBERTS, Assistant Examiner,

7. COMPOUNDS OF THE FORMULAE